Glioblastoma (GBM) is the most common and the most lethal brain cancer. The challenges inherent in developing effective GBM therapeutics include resistance to standard treatments such as radiation and chemotherapy, limited drug delivery into the tumor due to the Blood-Brain-Barrier (BBB), genetic and molecular heterogeneity, and a subpopulation of stem-like GBM cells (GSCs). Here, we propose a novel strategy that may overcome the above hurdles. Our recent studies have discovered that dopamine receptor subtype 2 (DRD2), a key receptor for dopamine signaling in the brain, promoted GBM growth and survival. Mechanistically, oncogenic DRD2 signaling in GBM activates c-MET receptor, a key regulator for cancer stem phenotype and GBM therapeutic resistance, via direct interaction between DRD2 and c-MET. Importantly, DRD2 inhibition via an FDA-approved DRD2 antagonist, which can freely pass the BBB, potently inactivated oncogenic signaling pathways, diminished clonogenic growth of GSCs, and impeded GBM growth. Based on these findings, we propose three Aims to validate the DRD2 targeting as new concept for the treatment of human GBM: 1) The mechanistic Aim will explore how the DRD2 targeting leads to tumor cell death and how inactivation of this axis can be reliably achieved in GBM. 2) The stratification Aim will identify disease subtypes and groups of patients that may be most responsive to the DRD2 targeting based on our finding that a subset of GBM tumors produces dopamine and these tumors are more addicted to oncogenic DRD2 signaling. 3) The goal of therapeutic Aim is the development and preclinical validation of DRD2 antagonists using mouse avatars bearing patient-derived GBM tumors.